Long-term objectives are to (1) identify novel drug candidates related to magainin peptide class with powerful anti-infective activity against pathogenic oral cavity flora; (2) use in vivo models to test magainins' role in preventing and/or treating root surface caries and periodontal diseases, and (3) determine magainin efficacy as a prophylactic and/or treatment intervention of oral cavity to reduce the incidence of systemic complications in immunocompromised patients. Zasloff described magainins, 21-27 amino acid peptides isolated from frog skin, with remarkable antibacterial, antifungal and antiparasitic activities. These peptides are a novel vertebrate host defense system, acting by membrane ion channel-forming mechanisms. Immunohistochemical and Western blot experiments suggest magainin-like peptides may be present in human saliva and salivary glands and function endogenously in containing oral flora. Our specific aims will be to (1) determine magainin effects on important oral bacteria; (2) determine dose-response and structure-activity relationship of new improved magainin derivatives; (3) produce analogs which resist breakdown by oral peptidases through amino acid substitutions; (4) determine if magainins exhibit therapeutic synergism against important oral flora with fluoride and other anti-infectives.